bims-polyam Biomed News
on Polyamines
Issue of 2019‒07‒07
twelve papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology


  1. Biochem J. 2019 Jun 27. pii: BCJ20190294. [Epub ahead of print]
    Schultz CR, Bupp CP, Rajasekaran S, Bachmann AS.
      We recently described a new autosomal dominant genetic disorder in a pediatric patient caused by a heterozygous de novo mutation in the ornithine decarboxylase 1 ( ODC1 ) gene. The new genetic disorder is characterized by global developmental delay, alopecia, overgrowth, and dysmorphic features. We hypothesized that this new mutation (c.1342 A>T) leads to a c-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells. ODC (E.C. 4.1.1.17) is a rate-limiting enzyme in the biosynthesis of polyamines (putrescine, spemidine, spermine) that plays a crucial role during embryogenesis, organogenesis, and tumorigenesis. In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year old patient contain large amounts of ODC protein and putrescine compared to primary dermal (neonatal and adult) fibroblast control cells. Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay. Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death. In conclusion, our patient and potentially other patients that carry a similar ODC1 gain-of-function mutation might benefit from treatment with DFMO, a drug with a good safety profile, to suppress the exceptionally high ODC activity and putrescine levels in the body.
    Keywords:  Bachmann-Bupp syndrome; DFMO; gain-of-function mutation; human genetic disease; ornithine decarboxylase; polyamines
    DOI:  https://doi.org/10.1042/BCJ20190294
  2. Alzheimers Res Ther. 2019 Jun 29. 11(1): 58
    Sandusky-Beltran LA, Kovalenko A, Ma C, Calahatian JIT, Placides DS, Watler MD, Hunt JB, Darling AL, Baker JD, Blair LJ, Martin MD, Fontaine SN, Dickey CA, Lussier AL, Weeber EJ, Selenica MB, Nash KR, Gordon MN, Morgan D, Lee DC.
      BACKGROUND: Tau stabilizes microtubules; however, in Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression.METHODS: Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology.
    RESULTS: Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain.
    CONCLUSION: These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.
    Keywords:  Alzheimer’s disease; Hippocampus; Polyamine dysregulation; Tau
    DOI:  https://doi.org/10.1186/s13195-019-0507-y
  3. Exp Dermatol. 2019 Jul 01.
    Lee YR, Lee J, Lew BL, Sim WY, Hong J, Chung BC.
      Hair loss, from the vertex or front of the head, generally occurs due to increased androgenic steroid levels. Androgenic steroids, particularly testosterone and dihydrotestosterone, are distributed differently across the vertex and occipital regions, and are involved in inducing ornithine decarboxylase expression. Therefore, we hypothesized that the distribution of polyamines may be altered in different scalp regions. For the overall metabolic profiling of polyamines in patients with hair loss, a liquid chromatography-mass spectrometry was used. We investigated the differential polyamine levels in different regions of the hair of patients with male-pattern baldness and those with female-pattern hair loss. The levels of most polyamines were higher in the vertex region than in the occipital region, and N-acetyl polyamine levels differed significantly. We proposed to test our hypothesis by profiling polyamines in human hair fiber to evaluate the distribution of metabolites in various regions of the scalp. This article is protected by copyright. All rights reserved.
    Keywords:  female-pattern hair loss; male-pattern baldness; occipital; polyamine; vertex
    DOI:  https://doi.org/10.1111/exd.13998
  4. Int J Mol Sci. 2019 Jun 30. pii: E3215. [Epub ahead of print]20(13):
    Hasanuzzaman M, Alhaithloul HAS, Parvin K, Bhuyan MHMB, Tanveer M, Mohsin SM, Nahar K, Soliman MH, Mahmud JA, Fujita M.
      Polyamines (PAs) are found in all living organisms and serve many vital physiological processes. In plants, PAs are ubiquitous in plant growth, physiology, reproduction, and yield. In the last decades, PAs have been studied widely for exploring their function in conferring abiotic stresses (salt, drought, and metal/metalloid toxicity) tolerance. The role of PAs in enhancing antioxidant defense mechanism and subsequent oxidative stress tolerance in plants is well-evident. However, the enzymatic regulation in PAs biosynthesis and metabolism is still under research and widely variable under various stresses and plant types. Recently, exogenous use of PAs, such as putrescine, spermidine, and spermine, was found to play a vital role in enhancing stress tolerance traits in plants. Polyamines also interact with other molecules like phytohormones, nitric oxides, trace elements, and other signaling molecules to providing coordinating actions towards stress tolerance. Due to the rapid industrialization metal/metalloid(s) contamination in the soil and subsequent uptake and toxicity in plants causes the most significant yield loss in cultivated plants, which also hamper food security. Finding the ways in enhancing tolerance and remediation mechanism is one of the critical tasks for plant biologists. In this review, we will focus the recent update on the roles of PAs in conferring metal/metalloid(s) tolerance in plants.
    Keywords:  Abiotic stress; amino acids; phytohormones; reactive oxygen species; stress signaling; toxic metal/metalloid(s)
    DOI:  https://doi.org/10.3390/ijms20133215
  5. Plant J. 2019 Jul 01.
    Shinohara S, Okamoto T, Motose H, Takahashi T.
      In Arabidopsis, spermine is produced in most tissues and has been implicated in stress response, while its structural isomer thermospermine is only in xylem precursor cells. Studies on acaulis5 (acl5), a mutant defective in the biosynthesis of thermospermine, have revealed that thermospermine plays a repressive role in xylem development through enhancement of mRNA translation of the SAC51 family. In contrast, the pao5 mutant defective in the degradation of thermospermine has high levels of thermospermine and shows increased salt tolerance, suggesting a role of thermospermine in salt stress response. Here we compared acl5 with a mutant of spermine synthase, spms, in terms of abiotic stress tolerance and found that acl5 was much more sensitive to sodium than the wild type and spms. A double mutant of acl5 and sac51-d, which suppresses the excessive xylem phenotype of acl5, recovered normal sensitivity while a quadruple T-DNA insertion mutant of the SAC51 family, which has an increased thermospermine level but shows excessive xylem development, showed increased salt sensitivity, unlike pao5. Together with the result that the salt tolerance of both wild-type and acl5 seedlings was improved by long-term treatment with thermospermine, we suggest a correlation of the salt tolerance with reduced xylem development rather than with the thermospermine level. We further found that the mutants containing high thermospermine levels showed increased tolerance to drought and heat stress, suggesting another role of thermospermine which may be common with that of spermine and secondary to that in restricting excess xylem development associated with salt hypersensitivity. This article is protected by copyright. All rights reserved.
    Keywords:   Arabidopsis thaliana ; salt tolerance; spermine; thermospermine; xylem
    DOI:  https://doi.org/10.1111/tpj.14448
  6. Food Sci Biotechnol. 2019 Aug;28(4): 1241-1245
    Yamada T, Park G, Node J, Ozaki K, Hiraiwa M, Kitaguchi Y, Kaneda K, Hiramoto S, Hinoi E.
      An imbalance in the sophisticated regulation between bone-resorbing osteoclasts and bone-forming osteoblasts leads to the pathogenesis and etiology of certain metabolic bone diseases including osteoporosis. Certain polyamines are related to the pathophysiology of some disorders, including Alzheimer's disease, infectious disease, cancer, and aging. Recently, we demonstrated that oral intake of polyamines (spermidine and spermine) prevented bone loss through preferential disturbance of osteoclastic activation in ovariectomy-induced mouse model of postmenopausal osteoporosis. Here, we showed that daily oral supplementation of a diet containing polyamine-rich Saccharomyces cerevisiae S631 significantly inhibited osteoclastic activation as well as reduction of bone volume in the cancellous bone without affecting uterine weight in ovariectomized mice. Our findings recommend that daily oral supplementation with polyamine-rich yeast diet would be beneficial for prophylaxis of metabolic bone diseases associated with abnormal osteoclast activation.
    Keywords:  Bone loss; Saccharomyces cerevisiae; Spermidine; Spermine
    DOI:  https://doi.org/10.1007/s10068-019-00561-4
  7. Environ Pollut. 2019 Jun 12. pii: S0269-7491(19)31099-1. [Epub ahead of print]252(Pt B): 941-949
    Yu Y, Zhou W, Liang X, Zhou K, Lin X.
      The accumulation of bound and conjugated polyamines (PAs) is an important protective trait in plants under adverse environmental conditions. However, their role in plant responses to aluminum (Al) stress remains largely unknown. In this study, we showed that Al treatment increased bound putrescine (Put) levels in the wheat root tips of Al-tolerant Xi Aimai-1, with little effect on its bound spermidine and conjugated PAs or that of Al-sensitive Yangmai-5. Terminating bound Put increments with a synthesis inhibitor (Phenanthroline, o-phen) exacerbated Al-induced root inhibition and callose production. However, it had no significant effect on Al uptake or distribution under Al stress. Instead, Al-induced reactive oxygen species (ROS) production and thus, oxidative damage, was greatly exacerbated by o-phen in the roots of Xi Aimai-1. Application of o-phen barely affected the two ROS generating enzymes (plasma membrane NADPH oxidase and cell wall-bound polyamine oxidase) in wheat roots. However, exogenous o-phen significantly reduced antioxidant enzyme (superoxide dismutase, ascorbate peroxidase, and catalase) activity, which positively correlated with the level of bound Put in Xi Aimai-1. These results clearly suggest that bound Put accumulation works to protect against Al-induced oxidative damage, possibly by maintaining antioxidant capacity in wheat.
    Keywords:  Aluminum; Antioxidant enzyme; Bound putrescine; Oxidative stress; Wheat
    DOI:  https://doi.org/10.1016/j.envpol.2019.06.045
  8. Ecotoxicol Environ Saf. 2019 Jun 26. pii: S0147-6513(19)30699-2. [Epub ahead of print]182 109378
    Alzahrani Y, Rady MM.
      Recently, the strategy of seed soaking has been successfully applied using extracts from different plant parts for healthy growth of plant under different environmental stresses. Compared to antioxidants like ascorbic acid (AsA) and glutathione (GSH) or polyamines (PAs) like spermine (SPM), spermidine (SPD), and putrescine (PUT), the effects of seed soaking using maize grain extract (MGE) on the biomass, productivity, phytohormones, and antioxidant defense system and its different components were examined with Cd2+-stressed wheat plants. In a preliminary study, seed soaking using AsA + GSH or PUT + SPD + SPM was more effective in increasing shoot fresh and dry weights, SPAD chlorophyll, and grain yield, and reducing malondialdehyde (MDA) content than individuals. In addition, MGE at 2% was more efficient than other concentrations. Therefore, they were selected for the main study. In the main study, compared to the control, seed soaking in AsA + GSH, PUT + SPD + SPM or MGE had positive effects on plant growth, yield, photosynthetic efficiency, contents and redox states of AsA and GSH, contents of PAs and plant hormones to varying degrees. Proline content and its metabolism enzymes activity, contents of soluble protein, N-compounds, soluble sugars, and α-tocopherol (α-TOC), and activities of antioxidant enzymes were not affected. However, contents of MDA and hydrogen peroxide (H2O2) were significantly reduced under normal conditions. Under Cd2+ stress (1.2 mM), along with the detrimental increases in the contents of MDA, H2O2 and Cd2+, contents of N-compounds, soluble sugars, proline content and its metabolism enzymes activities, AsA and GSH and their redox states, and polyamines, and activities of antioxidant enzymes were increased. In contrast, plant growth and yield, photosynthetic efficiency, soluble protein, and plant hormones were significantly reduced compared to the control. However, all of these attributes were significantly improved to varying degrees along with reduced contents of Cd2+, MDA, and H2O2 by seed soaking in AsA + GSH, PUT + SPD + SPM or MGE compared to the Cd2+-stressed control. Compared to AsA + GSH or PUT + SPD + SPM, seed soaking in MGE at 2% conferred the best results. Therefore, it is recommended to soak wheat seeds using MGE to improve plant growth and productivity by restricting the inhibitory influences of oxidative stress induced by Cd2+ stress.
    Keywords:  Antioxidant reducing power; Cadmium stress; Defense systems; Plant hormones; Proline and metabolism enzymes; Wheat productivity
    DOI:  https://doi.org/10.1016/j.ecoenv.2019.109378
  9. J Inherit Metab Dis. 2019 Jul 01.
    Ranucci G, Rigoldi M, Cotugno G, Bernabei S, Liguori A, Gasperini S, Goffredo B, Martinelli D, Monti L, Francalanci P, Candusso M, Parini R, Dionisi-Vici C.
      The increased survival of urea cycle disorders (UCDs) patients has led the attention to clinical manifestations that characterize the long-term disease course. Acute and chronic liver disease have been anecdotally reported since the very first description of UCDs. However a detailed analysis of long-term liver involvement in large patient cohorts is still needed. Chronic liver damage in UCDs has probably a multifactorial origin, but the specific underlying mechanisms of liver disease have not yet been well elucidated. In this study, we report on chronic liver involvement and on associated metabolic abnormalities in a large cohort of 102 UCD patients, followed by two reference centers in Italy. Chronic liver involvement was observed in over 60% of UCDs patients, and comparison between individual diseases showed a significant higher frequency in ASLD and in HHH syndrome with elevation of transaminases and of gamma-GT in ASLD, and of alpha-fetoprotein in HHH syndrome. Also, consistent with a chronic hepatic dysfunction, ultrasound examination revealed more pronounced abnormalities in ASLD and in HHH syndrome, when compared to other UCDs. Our study highlights in a large UCDs patients' cohort that chronic liver disease is a common finding in UCDs, often with a distinct phenotype between different diseases. Furthers studies are needed to elucidate the specific involvement of different metabolic pathways in the pathogenesis of liver dysfunction in UCDs. This article is protected by copyright. All rights reserved.
    Keywords:  argininosuccinate lyase deficiency; chronic liver disease; hyperornithinemia-hyperammonemia-homocitrullinemia syndrome; incomplete septal cirrhosis; lean nonalcoholic fatty liver disease; metabolic syndrome; urea cycle disorders
    DOI:  https://doi.org/10.1002/jimd.12144
  10. J Inherit Metab Dis. 2019 Jul 03.
    Waisbren SE, Stefanatos AK, Kok TMY, Ozturk-Hismi B.
      Urea cycle disorders (UCDs) are rare inherited metabolic conditions that impair the effectiveness of the urea cycle responsible for removing excess ammonia from the body. The estimated incidence of UCDs is 1:35,000 births, or approximately 113 new patients with UCD per year. This review summarizes neuropsychological outcomes among patients with the 8 UCDs in reports published since 1980. Rates of intellectual disabilities published before (and including) 2000 and after 2000 were pooled and compared for each UCD. Since diagnoses for UCDs tended to occur earlier and better treatments became more readily available after the turn of the century, this assessment will characterize the extent that current management strategies have improved neuropsychological outcomes. The pooled sample included data on cognitive abilities of 1649 individuals reported in 58 citations. A total of 556 patients (34%) functioned in the range of intellectual disabilities. The decline in the proportion of intellectual disabilities in 6 disorders, ranged from 7% to 41%. Results from various studies differed and the cohorts varied with respect to age at symptom onset, age at diagnosis and treatment initiation, current age, severity of the metabolic deficiency, management strategies, and ethnic origins. The proportion of cases with intellectual disabilities ranged from 9% to 65% after 2000 in the 7 UCDs associated with cognitive deficits. Positive outcomes from some studies suggest that it is possible to prevent or reverse the adverse impact of UCDs on neuropsychological functioning. It is time to "raise the bar" in terms of expectations for treatment effectiveness. This article is protected by copyright. All rights reserved.
    Keywords:  intellectual disabilities; neuropsychological outcomes; urea cycle disorders
    DOI:  https://doi.org/10.1002/jimd.12146
  11. Amino Acids. 2019 Jul 03.
    Charlier D, Bervoets I.
      Already very early, the study of microbial arginine biosynthesis and its regulation contributed significantly to the development of new ideas and concepts. Hence, the term "repression" was proposed by Vogel (The chemical basis of heredity, The John Hopkins Press, Baltimore, 1957) (in opposition to induction) to describe the relative decrease in acetylornithinase production in Escherichia coli cells upon arginine supplementation, whereas the term "regulon" was coined by Maas and Clark (J Mol Biol 8:365-370, 1964) for the ensemble of arginine biosynthetic genes dispersed over the E. coli chromosome but all subjected to regulation by the trans-acting argR gene product. Since then, unraveling of the molecular mechanisms controlling arginine biosynthesis, catabolism, and transport in and out the cell, have revealed moonlighting activities of enzymes and transcriptional regulators that generate unexpected interconnections between at first sight totally unrelated cellular processes, and have continued to replenish scientific knowledge and stimulated creative thinking. Furthermore, arginine is much more than just a common amino acid for protein synthesis. It may also be used as sole source of nitrogen by E. coli and a source of nitrogen, carbon and energy by many other bacteria. It is a substrate for the synthesis of polyamines, and important for the extreme acid resistance of E. coli. Furthermore, the guanidino group of arginine is well suited to engage in multiple interactions involving hydrogen bonds and ionic interactions with proteins and nucleic acids. Here, we combine major historical discoveries with current state of the art knowledge on arginine biosynthesis, catabolism and transport, and especially the regulation of these processes in E. coli, with reference to other microorganisms.
    Keywords:  Arginine; Feedback inhibition; Leucine; Lysine; Protein-DNA interactions; Transcriptional regulation
    DOI:  https://doi.org/10.1007/s00726-019-02757-8
  12. J Pediatr Endocrinol Metab. 2019 Jun 27. pii: /j/jpem.ahead-of-print/jpem-2019-0146/jpem-2019-0146.xml. [Epub ahead of print]
    Manta-Vogli PD, Schulpis KH, Loukas YL, Dotsikas Y.
      Background Arginine family amino acids (AFAAs) include glutamine (Gln) plus glutamate (Glu), ornithine (Orn), proline (Pro), citrulline (Cit) and arginine (Arg). We aimed to quantitate these amino acids in the blood of full-term infants in relation to their birth weight (BW) perinatally. Methods Breastfeeding full-term infants (n = 2000, 1000 males, 1000 females) with a BW of 2000-4000 g were divided into four equal groups: group A, 2000-2500 g; B, 2500-3000 g; C, 3000-3500 g and D, 3500-4000 g. Blood samples as dried blood spots (DBS) were collected on the third day of life and analyzed via a liquid chromatography tandem mass spectrometry (LC-MS/MS) protocol. Results Gln plus Glu mean values were found to be statistically significantly different between males and females in all studied groups. The highest values of these amino acids were detected in both males and females in group D. Orn mean values were found to be statistically significantly different between males and females of the same BW in all groups except the last one. The lower mean value was determined in group A, whereas the highest was determined in group D. Cit and Arg mean values were determined to be almost similar in all studied groups. Conclusions Gln plus Glu and Orn blood concentrations were directly related to infants' BW. Conversely, Cit and Arg did not vary significantly in all groups.
    Keywords:  arginine family amino acids; citrulline; glutamine; neonates; ornithine
    DOI:  https://doi.org/10.1515/jpem-2019-0146